Cardiovascular disease remains the number one cause of morbidity and mortality in the United States despite advances in prevention, diagnosis and treatment. Over 5 million people in the U.S. carry the diagnosis of heart failure. It is estimated that there will be over 250,000 new cases of heart failure diagnosed in the year 2000 and nearly 400,000 deaths will be attributed to the disease. Despite the salutary effects of new therapies, the disease remains progressive and patients eventually develop worsening symptoms; the five-year survival of patients diagnosed with heart failure is less than 50%. The only definitive therapy remains cardiac transplantation. However, only an average of 2600 patients receive a transplant each year because of limitations in donor supply. Clearly additional means of treating patients with progressive and/or fulminant heart failure must be developed. For patients who do receive donor hearts, there remains a substantial risk for donor heart failure due to ischemia-reperfusion, vasculopathy and transplant rejection. While the latter can be managed by immunosuppressive drugs, there remain the early phase problems that gene transfer may well provide assistance in reducing these risks. The proposed PEGT, entitled Cardiovascular Gene Therapy Center, has continued to emerge as major effort at the University of Pittsburgh and brings together of wealth of talent to address this difficult problem. In this renewal application our plans are (i) to continue to our efforts to treat intimal hyperplasia using vector mediated delivery to AV grafts using adenovirus iNOS gene therapy, (ii) to develop an AAV-6-SERCA2 gene vector for enhancing calcium transients to improve cardiomyocyte function in of heart failure patients on LVAD (iii) to develop HSV heme oxygenase gene vectors retargeted to endothelial cell receptors as a treatment for ischemia-reperfusion, (iv) to develop gene therapies using AAV and other gene delivery systems to prevent extracellular matrix remodeling of cardiac tissue as a deterrent to heart failure and (v) to develop iNOS gene therapy for treatment of transplant vasculopathy. Together these highly integrated projects and supporting core programs in imaging, vector construction and manufacture, clinical trials oversight, and training should bring new interventions to the clinics that may eventually provide new hope for patients with this disease.